5-35644519-T-C

Variant names:

• chr5-35644519-T-C
• rs7706444
• NM_024867.4:c.579T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024867.4(SPEF2):​c.579T>C​(p.Ile193Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,591,038 control chromosomes in the GnomAD database, including 356,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37557 hom., cov: 32)
  • Exomes 𝑓: 0.66 (318968 hom.)
• Consequence: SPEF2 NM_024867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.13
• Publications: 19 publications found

Genes affected

SPEF2 (HGNC:26293): (sperm flagellar 2) Involved in sperm axoneme assembly. Located in sperm flagellum. Implicated in spermatogenic failure 43. [provided by Alliance of Genome Resources, Apr 2022]

SPEF2 Gene-Disease associations (from GenCC):

• spermatogenic failure 43

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-35644519-T-C is Benign according to our data. Variant chr5-35644519-T-C is described in ClinVar as Benign. ClinVar VariationId is 403472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEF2	NM_024867.4	c.579T>C	p.Ile193Ile	synonymous_variant	Exon 4 of 37	ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8	c.579T>C	p.Ile193Ile	synonymous_variant	Exon 4 of 37	1	NM_024867.4	ENSP00000348314.3

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106056 AN: 151918 Hom.: 37496 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.674

GnomAD2 exomes AF: 0.707 AC: 162203 AN: 229368 AF XY: 0.703

Gnomad AFR exome AF: 0.779

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.866

Gnomad FIN exome AF: 0.628

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.680

GnomAD4 exome AF: 0.663 AC: 953405 AN: 1439002 Hom.: 318968 Cov.: 33 AF XY: 0.666 AC XY: 476156 AN XY: 715286

African (AFR) AF: 0.779 AC: 24858 AN: 31918

American (AMR) AF: 0.781 AC: 30514 AN: 39076

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 16486 AN: 25004

East Asian (EAS) AF: 0.875 AC: 34534 AN: 39488

South Asian (SAS) AF: 0.810 AC: 66353 AN: 81874

European-Finnish (FIN) AF: 0.633 AC: 33431 AN: 52854

Middle Eastern (MID) AF: 0.656 AC: 3667 AN: 5590

European-Non Finnish (NFE) AF: 0.637 AC: 703395 AN: 1103938

Other (OTH) AF: 0.678 AC: 40167 AN: 59260

GnomAD4 genome AF: 0.698 AC: 106183 AN: 152036 Hom.: 37557 Cov.: 32 AF XY: 0.699 AC XY: 51961 AN XY: 74298

African (AFR) AF: 0.775 AC: 32134 AN: 41488

American (AMR) AF: 0.725 AC: 11067 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2290 AN: 3472

East Asian (EAS) AF: 0.868 AC: 4476 AN: 5156

South Asian (SAS) AF: 0.826 AC: 3984 AN: 4822

European-Finnish (FIN) AF: 0.609 AC: 6417 AN: 10536

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43738 AN: 67988

Other (OTH) AF: 0.677 AC: 1429 AN: 2110

Alfa AF: 0.657 Hom.: 62647

Bravo AF: 0.707

Asia WGS AF: 0.830 AC: 2886 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Spermatogenic failure 43 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.36
DANN	Benign	0.34
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7706444; hg19: chr5-35644621; COSMIC: COSV108035797; COSMIC: COSV108035797;